The medical condition referred to as “dry eye” is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface associated with symptoms of ocular discomfort.
Dry eye includes two major classes: (i) aqueous tear deficient dry eye (ADDE), and (ii) evaporative dry eye (EDE).
ADDE refers mainly to a failure of sufficient tear secretion due to lacrimal dysfunction. ADDE has two major subclasses: (i) Sjogren's Syndrome dry eye (SSDE), and (ii) non-SS dry eye (such as in Graft-versus-Host Disease (GvHD) or in diabetes mellitus or non-specific dry eye).
EDE may be: (i) intrinsic, due to diseases affecting lid structures or dynamics, or (ii) extrinsic, in which ocular surface disease occurs due to some extrinsic exposure, such as topical drug preservatives, contact lens wear, pterygium, pinguecula, exposure to air conditioned environments, or vitamin A deficiency.
Alternatively or additionally, Dry eye is sometimes caused by Meibomian gland dysfunction.
The most prescribed medication for dry eye is Restasis (cyclosporine drops) with a 60% market share. This product works for 15% of patients vs 5% whom respond to placebo. It has several significant side effects and is not well tolerated.
As used in this specification and the accompanying claims the term “corneal ulcer” refers to a medical condition in which the corneal epithelium, and/or stroma are lysed. Corneal ulcers are caused, for example, by infections and/or physical force. In the case of infections, corneal ulcers often result from the activation and hypersecretion of collagenolytic enzyme. The ulcerative process is often linked to collagenolytic enzymes such as bacterial collagenase and/or matrix metalloproteases (MMPs). Corneal ulcers often result from keratitis.
Keratitis is an inflammation of cornea and is caused, for example, by contact lens wear, injury to the eye, infections and environmental causes.
Corneal abrasions are similar in etiology to corneal ulcers but are restricted to the epithelial layer of the cornea without penetration to the stroma. Corneal abrasions are also referred to as “scratch of the cornea” and may be caused by infection and/or trauma. They usually are associated with or known as superficial keratitis.
The changes in the extracellular environment caused by the degradation of stromal collagen promote ulcers. Such conditions produce a vicious circle of activation of corneal stromal cells and degradation of corneal stroma. When the bacteria are killed by antibiotics, secretion of bacterial collagenase is suppressed, and direct corneal stroma degradation due to the bacteria is suppressed. However, since most antibiotics cannot suppress activation of corneal stromal cell caused by the biological signals once transmitted from bacteria to corneal stromal cells, progression of ulcer is clinically observed from time to time.
The corneal/conjunctival diseases, including a repeated erosion of the cornea and a prolonged corneal epithelial deficiency, are associated with such disorders. The repairing process of the corneal/conjunctival epithelial disorders involves the coverage of the epithelial deficiency by the migration of corneal epithelial cells, followed by a subsequent cell division and differentiation, resulting in reconstitution of normal cornea and conjunctiva.
Corneal anesthesia and congenital corneal anesthesia usually develop into or are regarded as neurotrophic keratopathy. Neurotrophic keratopathy is a degenerative corneal disease induced by an impairment of the trigeminal nerve. Impairment or loss of corneal sensory innervation is sometimes responsible for corneal epithelial defects, ulcers, and perforations.
A pterygium (sometimes referred to as Surfer's eye) is a non-cancerous growth that starts in the clear, thin tissue (conjunctiva) of the eye. This growth covers the white part of the eye (sclera), and extends onto the cornea. It is slightly or significantly raised, and often contains visible blood vessels (also known as hyperemia). The problem may occur in one or both eyes. Pterygium may become inflamed and cause burning, irritation, or a feeling like there's something foreign in the eye. Vision may be affected if the growth extends far enough onto the cornea. There is at present no known curative treatment for pterygium other than surgery. There is a very high recurrence rate for pterygium post surgery. Formulations of chemotherapy or immune-suppressive eye-drops (such as mitomycin or cyclosporine) are often used in the eye to prevent recurrence after surgery. Surgery often results in scarring which can affect vision. The cause of pterygium is not certain. It has been linked to prolonged sun exposure through ultraviolet induced mechanisms. It has also been linked to viral processes such as HPV. It is considered by some to be a neoplastic process or one able to transform into a cancerous condition.
A pinguecula is a yellowish, slightly-raised thickening of the conjunctiva on the sclera. According to some opinions, a pinguecula always precedes the formation of a pterygium. Pingueculae typically occur on the part of the sclera that is between the eyelids, and therefore is exposed to the sun. In some cases pingueculae become swollen and inflamed, a condition called pingueculitis. This is usually treated with topical steroids or topical anti-inflammatory drugs. Frequently, pinguecula can lead to the formation of pterygium. There is at present no known curative treatment for pinguecula other than surgery. There is a very high recurrence rate for pingueculae post surgery. Formulations of chemotherapy or immune-suppressive eye-drops (such as mitomycin or cyclosporine) are often used in the eye to prevent recurrence after surgery. Surgery often results in scarring which can affect vision.
Uveitis is inflammation of the middle layer of the eye, called the uvea or uveal tract. The uvea consists of the middle, pigmented, vascular structures of the eye, and includes the iris, ciliary body, and choroid. Uveitis can affect the anterior segment of the eye or the posterior segment of the eye. When it affects the anterior segment, it is usually referred to as anterior uveitis. In western countries, anterior uveitis accounts for between 50% and 90% of uveitis cases, while in Asian countries the proportion drops to be between 28% and 50%. Uveitis is estimated to be responsible for approximately 10-20% of the cases of blindness in the United States. The cause of uveitis is generally infectious (bacterial or viral infection), autoimmune-disease-related, trauma related or idiopathic. Genetic factors can act as a predisposing factor for this difficult-to-treat condition. While uveitis is sometimes treated systemically, localized treatments will usually differ when treating anterior segment or posterior segment uveitis.
Blepharitis is a swelling or inflammation of the eyelids. It often contributes to dry eye syndrome and can cause many ocular symptoms such as itching, grittiness, photophobia, eyelid crusting and red, swollen eyes. Blepharitis prevalence increases with age. Amongst other factors, it may be caused by an infection, allergies or headlice. It is often associated with Meibomian gland dysfunction. It is typically treated using antibiotics or anti-inflammatory drugs such as steroids or a combination of both.
Pink eye, also referred to as conjunctivitis, madras eye, red eye, allergic conjunctivitis or non-specific conjunctivitis is a redness and swelling of the conjunctiva often resulting from inflammation or infection. It is often treated using antibiotics or anti-inflammatory drugs including steroids.
Keratoconus is a degenerative (thinning) disorder of the cornea that causes visual distortion. It is typically treated with various kinds of contact lenses that correct vision, with plastic rings inserted into the midlayer of the cornea to flatten it or with corneal crosslinking. In advanced cases corneal transplant surgery becomes necessary.
In the prior art, dipyridamole {2,6-bis(diethanolamino)-4,8-dipiperidinopyrimido [5,4-d]pyrimidine}, closely related substituted pyrimido-pyrimidines, and their preparation are taught by Fischer in U.S. Pat. No. 3,031,450 (hereinafter referred to as Fischer '450). Dipyridamole was introduced as a coronary vasodilator in the early 1960s, and is well known to have platelet aggregation inhibitor properties due to the inhibition of adenosine uptake. Subsequently, dipyridamole was shown to reduce thrombus formation in a study of arterial circulation of the brain in a rabbit model. These investigations led to its use as an anti-thrombotic agent. Dipyridamole soon became the therapy of choice for such applications as stroke prevention, maintaining the patency of coronary bypass and valve-replacement, as well as for treatment prior to coronary angioplasty.
In Patent Publication No. EP 0234854 B1 by Gilbard et al. (hereinafter referred to as Gilbard '854), it is suggested that cyclic cAMP functions as a second messenger for exocytosis in the lacrimal gland, and acts to increase tear secretion. cAMP is degraded by phosphodiesterases. It is therefore thought that suppressing phosphodiesterases can result in increased intracellular cAMP levels, and thus enhance tear secretion. Dipyridamole is believed to act as a phosphodiesterase inhibitor in some human cells, and is thought to exert some of its cardiovascular benefits via this mechanism.
However, on page 19 of Patent Publication No. WO 2007/140181 by Leung (hereinafter referred to as Leung '181), it is disclosed that there was a negligible effect on cAMP levels after the addition of dipyridamole in comparison to a control. Only a combination of caffeine and dipyridamole yielded the desired effect of decreasing cAMP in-vitro, which is assumed to indicate increased cellular uptake of cAMP through upregulation of the adenosine-3 receptor.
In WO 2010056710, Defterios teaches that dipyridamole increases nitric oxide levels thus precluding its use as single agent therapy for treating inflammatory eye disorders. Defterios teaches to overcome this problem through combining benzisoselenazole with dipyridamole since benzisoselenazole may decrease nitrix oxide (NO) formed during treatment with dipyridamole resulting in tolerability of a therapeutically effective amount. Thus Defterios teaches against the use of dipyridamole monotherapy for eye disorders.
Podos (in Invest. Opthalmol. Visual Sci. June 1979 p. 646-648) investigated the effect of dipyridamole in treatment of ocular inflammatory disease. He found that systemically administered dipyridamole had a significant beneficial effect however topically administered dipyridamole (in liquid formulation) was ineffective.